The main physical advantage of proton radiation therapy is the finite range of protons in the patient. However, proton treatment planning and delivery, as practiced today, is affected by considerable uncertainties in the range and therefore in the position of the distal dose fall-off region. Our overall goal is to utilize the physical proton advantage, i.e., the range, to its full extent in the clinic. We hypothesize that, mainly through the use of advanced imaging technology, we can reduce range uncertainties substantially, and control the depth position of the dose delivered to the patient to within 1 mm in the quasi-static case and within 3 mm in the presence of intra-fractional motion. We further hypothesize that this will lead to substantially improved target coverage and/or reduced dose to nearby critical structures. To meet the overall goal and test the hypotheses we will strive to achieve 3 Specific Aims. Aim 1 is the reduction of range uncertainties in the static scenario. It involves the reduction of CT metal artifacts through a filtering approach and the use of higher energies. It also addresses the conversion of CT numbers to stopping powers, which are needed for accurate dose calculation. Monte Carlo dose calculation methods will be developed. We will not only aim to calculate the proton range with great precision, but also to investigate range degradation due to tissue heterogeneities, which leads to a reduced steepness of the distal dose fall-off. Aim 2 is range control in the presence of organ motion. Here we will introduce spatio-temporal (4D) imaging techniques to analyze motion characteristics, and simulate organ motion in a numerical phantom. We will focus on gating strategies to mitigate the effects of the motion. We will also aim to improve positioning and immobilization accuracies, for example with optical imaging techniques. The third aim is to validate the achievable level of accuracy. This will be done in three ways. First we will investigate the feasibility and utility of in-vivo measurements using PET/CT scans taken directly after a proton treatment fraction. We will also do phantom measurements, both in a static phantom and in a biological motion phantom (swine lung). Finally, we will measure the residual range of an energetic proton beam after traversing the patient, and compare it with the expected value. All Aims are generally applicable to both passively scattered proton therapy and IMPT. Overall this project will show to what degree the primary physical advantage of protons (i.e., the finite range) can be translated into a dosimetric advantage in patients. The clinical relevance of this will be studied in Project 1 and Project 2.